ClinVar Genomic variation as it relates to human health
NM_000162.5(GCK):c.572G>A (p.Arg191Gln)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000162.5(GCK):c.572G>A (p.Arg191Gln)
Variation ID: 283358 Accession: VCV000283358.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p13 7: 44149976 (GRCh38) [ NCBI UCSC ] 7: 44189575 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 20, 2018 May 7, 2024 Apr 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000162.5:c.572G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000153.1:p.Arg191Gln missense NM_001354800.1:c.572G>A NP_001341729.1:p.Arg191Gln missense NM_033507.3:c.575G>A NP_277042.1:p.Arg192Gln missense NM_033508.3:c.569G>A NP_277043.1:p.Arg190Gln missense NC_000007.14:g.44149976C>T NC_000007.13:g.44189575C>T NG_008847.2:g.53195G>A LRG_1074:g.53195G>A LRG_1074t1:c.572G>A LRG_1074p1:p.Arg191Gln LRG_1074t2:c.575G>A LRG_1074p2:p.Arg192Gln - Protein change
- R192Q, R191Q, R190Q
- Other names
- NM_000162.5(GCK):c.572G>A
- p.Arg191Gln
- Canonical SPDI
- NC_000007.14:44149975:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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GCK | - | - |
GRCh38 GRCh37 |
1080 | 1106 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Nov 19, 2023 | RCV000711776.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 2, 2022 | RCV002285302.2 | |
Pathogenic (2) |
reviewed by expert panel
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Apr 19, 2024 | RCV002222471.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2022 | RCV002347992.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Apr 19, 2024)
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reviewed by expert panel
Method: curation
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Monogenic diabetes
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Monogenic Diabetes Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV005040698.1 First in ClinVar: May 07, 2024 Last updated: May 07, 2024 |
Comment:
The c.605T>G variant in the glucokinase gene, GCK, causes an amino acid change of methionine to arginine at codon 202 (p.(Met202Arg)) of NM_000162.5. GCK is … (more)
The c.605T>G variant in the glucokinase gene, GCK, causes an amino acid change of methionine to arginine at codon 202 (p.(Met202Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.873, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 39 unrelated individuals with hyperglycemia (PS4; PMID: 30259503, 29927023, 29510678, 29207974, 29056535, 27256595, 25953829, 25555642, 24918535, 20337973, 19309449, 11508276, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and three-generation, dominant family history of diabetes or hyperglycemia in a family not used for PP1) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 13 informative meioses in one family with MODY (PP1_Strong; internal lab contributors). Another missense variant, c.571C>T p.(Arg191Trp), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.(Arg191Gln) (PM5_Supporting). In summary, c.572G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP3, PP2, PM2_Supporting, PS4, PP1_Strong, PP4_Moderate, PM5_Supporting. (less)
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Uncertain significance
(Sep 21, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000335392.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Likely pathogenic
(Sep 26, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV000842172.2
First in ClinVar: Oct 20, 2018 Last updated: Jan 26, 2021 |
Comment:
Not found in the total gnomAD dataset, and the data is high quality. This variant has been found in multiple unrelated patients that meet standard … (more)
Not found in the total gnomAD dataset, and the data is high quality. This variant has been found in multiple unrelated patients that meet standard diagnostic criteria for the relevant disease. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. (less)
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Pathogenic
(Oct 07, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001782913.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Comment:
Not observed in large population cohorts (Lek et al., 2016; McVean et al., 2012; Exome Variant Server); This variant is associated with the following publications: … (more)
Not observed in large population cohorts (Lek et al., 2016; McVean et al., 2012; Exome Variant Server); This variant is associated with the following publications: (PMID: 31957151, 29207974, 29056535, 29510678, 24804978, 19309449, 16444761, 22060211, 19790256, 20337973, 24918535, 25555642, 27256595, 11508276) (less)
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Pathogenic
(Mar 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Monogenic diabetes
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002500417.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
Variant summary: GCK c.572G>A (p.Arg191Gln) results in a conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Four … (more)
Variant summary: GCK c.572G>A (p.Arg191Gln) results in a conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251110 control chromosomes (gnomAD). c.572G>A has been reported in the literature in multiple individuals affected with Monogenic Diabetes and the variant seggregated with the disease (example: Pruhova_2010, Codner_2009, Codner_2006, and Massa_2001). Another two variants affecting the same amino acid residue (p.R191L, p.R191W) are associated with MODY in HGMD. These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1), likely pathogenic (n=1) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 02, 2022)
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criteria provided, single submitter
Method: research
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Maturity-onset diabetes of the young type 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Geisinger Clinic, Geisinger Health System
Accession: SCV002562182.1
First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
Comment:
PP3, PP2, PM2, PS4, PP1_Strong, PP4_Moderate, PM5_Supporting
Number of individuals with the variant: 1
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Pathogenic
(Nov 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002138629.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 191 of the GCK protein (p.Arg191Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 191 of the GCK protein (p.Arg191Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with maturity onset diabetes of the young (PMID: 16444761, 27256595, 29510678, 30259503). ClinVar contains an entry for this variant (Variation ID: 283358). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GCK protein function with a negative predictive value of 80%. This variant disrupts the p.Arg191 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23295292, 27269892). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Maturity onset diabetes mellitus in young
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002650655.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R191Q pathogenic mutation (also known as c.572G>A), located in coding exon 5 of the GCK gene, results from a G to A substitution at … (more)
The p.R191Q pathogenic mutation (also known as c.572G>A), located in coding exon 5 of the GCK gene, results from a G to A substitution at nucleotide position 572. The arginine at codon 191 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been described in the heterozygous state in several unrelated individuals with maturity-onset diabetes of the young (MODY), type 2 (Caetano LA et al. Arq Bras Endocrinol Metabol, 2012 Nov;56:519-24; Pruhova S et al. Pediatr Diabetes, 2010 Dec;11:529-35; Codner E et al. Pediatr Diabetes, 2009 Sep;10:382-8; Codner E et al. Diabetes Metab Res Rev;22:348-55; Fulcoli FG et al. Nat Commun, 2016 06;7:11688; Aykut A et al. Gene, 2018 Jan;641:186-189; Yorifuji T et al. Pediatr Diabetes, 2018 11;19:1164-1172; Massa O et al. Diabetologia, 2001 Jul;44:898-905; Li X et al. BMC Pediatr, 2018 03;18:101; Al-Kandari H et al. Sci Rep, 2021 08;11:16060). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is expected to be causative of maturity-onset diabetes of the young (MODY), type 2 and permanent neonatal diabetes; however, its clinical significance for GCK-related neonatal hyperinsulinemic hypoglycemia is unclear. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts. | Mirshahi UL | American journal of human genetics | 2022 | PMID: 36257325 |
Identification of Maturity-Onset-Diabetes of the Young (MODY) mutations in a country where diabetes is endemic. | Al-Kandari H | Scientific reports | 2021 | PMID: 34373539 |
The importance of combined NGS and MLPA genetic tests for differential diagnosis of maturity onset diabetes of the young. | Komazec J | Endokrynologia Polska | 2019 | PMID: 30259503 |
Genetic basis of early-onset, maturity-onset diabetes of the young-like diabetes in Japan and features of patients without mutations in the major MODY genes: Dominance of maternal inheritance. | Yorifuji T | Pediatric diabetes | 2018 | PMID: 29927023 |
Genetic and clinical characteristics of Chinese children with Glucokinase-maturity-onset diabetes of the young (GCK-MODY). | Li X | BMC pediatrics | 2018 | PMID: 29510678 |
Analysis of the GCK gene in 79 MODY type 2 patients: A multicenter Turkish study, mutation profile and description of twenty novel mutations. | Aykut A | Gene | 2018 | PMID: 29056535 |
Spectrum of mutations in monogenic diabetes genes identified from high-throughput DNA sequencing of 6888 individuals. | Bansal V | BMC medicine | 2017 | PMID: 29207974 |
GCK mutations in Chinese MODY2 patients: a family pedigree report and review of Chinese literature. | Ping Xiao Y | Journal of pediatric endocrinology & metabolism : JPEM | 2016 | PMID: 27269892 |
Rebalancing gene haploinsufficiency in vivo by targeting chromatin. | Fulcoli FG | Nature communications | 2016 | PMID: 27256596 |
GCK gene mutations are a common cause of childhood-onset MODY (maturity-onset diabetes of the young) in Turkey. | Haliloglu B | Clinical endocrinology | 2016 | PMID: 27256595 |
Molecular genetic testing of patients with monogenic diabetes and hyperinsulinism. | Bennett JT | Molecular genetics and metabolism | 2015 | PMID: 25555642 |
Genetic variability of GCKR alters lipid profiles in children with monogenic and autoimmune diabetes. | Tracz A | Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association | 2014 | PMID: 24918535 |
Molecular and clinical characterization of glucokinase maturity-onset diabetes of the young (GCK-MODY) in Japanese patients. | Kawakita R | Diabetic medicine : a journal of the British Diabetic Association | 2014 | PMID: 24804978 |
Incretin effect and glucagon responses to oral and intravenous glucose in patients with maturity-onset diabetes of the young--type 2 and type 3. | Østoft SH | Diabetes | 2014 | PMID: 24677712 |
Incidental mild hyperglycemia in children: two MODY 2 families identified in Brazilian subjects. | Caetano LA | Arquivos brasileiros de endocrinologia e metabologia | 2012 | PMID: 23295292 |
Comprehensive molecular analysis of Japanese patients with pediatric-onset MODY-type diabetes mellitus. | Yorifuji T | Pediatric diabetes | 2012 | PMID: 22060211 |
Glucokinase diabetes in 103 families from a country-based study in the Czech Republic: geographically restricted distribution of two prevalent GCK mutations. | Pruhova S | Pediatric diabetes | 2010 | PMID: 20337973 |
Mild fasting hyperglycemia in children: high rate of glucokinase mutations and some risk of developing type 1 diabetes mellitus. | Codner E | Pediatric diabetes | 2009 | PMID: 19309449 |
Glucokinase mutations in young children with hyperglycemia. | Codner E | Diabetes/metabolism research and reviews | 2006 | PMID: 16444761 |
Glucokinase (GCK) mutations in hyper- and hypoglycemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy. | Gloyn AL | Human mutation | 2003 | PMID: 14517946 |
High prevalence of glucokinase mutations in Italian children with MODY. Influence on glucose tolerance, first-phase insulin response, insulin sensitivity and BMI. | Massa O | Diabetologia | 2001 | PMID: 11508276 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GCK | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/572070cd-f397-46ce-86c0-08a594ad4b36 | - | - | - | - |
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Text-mined citations for rs886042610 ...
HelpRecord last updated May 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.